Biomedical subjects

Bastiaan T Heijmans

Publications and source records attributed to Bastiaan T Heijmans.

14 recordsLinked to original sources

PubMed2006

Lipoprotein particle profiles mark familial and sporadic human longevity.

BACKGROUND: Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population. METHODS AND FINDINGS: NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10(-3)) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007). CONCLUSIONS: Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.

Aged↗

PubMed2005

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions.

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.

Adolescent↗

PubMed2005

Reduced insulin/IGF-1 signalling and human longevity.

Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress. In D. melanogaster and mice, the long-lived phenotype of several IIS mutants is restricted to females. Here, we analysed the relationship between IIS signalling, body height and longevity in humans in a prospective follow-up study. Based on the expected effects (increased or decreased signalling) of the selected variants in IIS pathway components (GHRHR, GH1, IGF1, INS, IRS1), we calculated composite IIS scores to estimate IIS pathway activity. In addition, we analysed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat and IRS1 SNP. In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower (P = 0.007) and mortality 0.80-fold reduced (P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms.

Aged↗

PubMed2005

Sex-limited genome-wide linkage scan for body mass index in an unselected sample of 933 Australian twin families.

Genes involved in pathways regulating body weight may operate differently in men and women. To determine whether sex-limited genes influence the obesity-related phenotype body mass index (BMI), we have conducted a general nonscalar sex-limited genome-wide linkage scan using variance components analysis in Mx (Neale, 2002). BMI measurements and genotypic data were available for 2053 Australian female and male adult twins and their siblings from 933 families. Clinical measures of BMI were available for 64.4% of these individuals, while only self-reported measures were available for the remaining participants. The mean age of participants was 39.0 years of age (SD 12.1 years). The use of a sex-limited linkage model identified areas on the genome where quantitative trait loci (QTL) effects differ between the sexes, particularly on chromosome 8 and 20, providing us with evidence that some of the genes responsible for BMI may have different effects in men and women. Our highest linkage peak was observed at 12q24 (-log10p = 3.02), which was near the recommended threshold for suggestive linkage (-log10p = 3.13). Previous studies have found evidence for a quantitative trait locus on 12q24 affecting BMI in a wide range of populations, and candidate genes for noninsulin-dependent diabetes mellitus, a consequence of obesity, have also been mapped to this region. We also identified many peaks near a -log10p of 2 (threshold for replicating an existing finding) in many areas across the genome that are within regions previously identified by other studies, as well as in locations that harbor genes known to influence weight regulation.

Body Mass Index↗

PubMed2004

Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level.

Interleukin-10 (IL10) is a cytokine with key regulatory and anti-inflammatory function involved in the pathogenesis of various diseases. Although the large interindividual differences in the production of IL10 have been extensively associated with polymorphisms and haplotypes of the IL10 gene, surprisingly little evidence exists that this variation is actually dictated by IL10 haplotypes. Using the technique of allele-specific transcript quantification, the ratio between two alleles (A and G) of the IL10 gene was characterized in 15 healthy heterozygous individuals. Two groups were identified whereby donors in group 1 exhibited a 1 : 1 ratio, whereas those in group 2 exhibited a ratio>1 (P<0.0017). We found that donors heterozygous for haplotype IL10.2 (one of the four ancient IL10 haplotypes) were only prevalent in the group that showed higher allelic expression ratios. In this study we show that IL10 alleles are indeed differentially transcribed in cells from heterozygous individuals and that IL10 haplotypes dictate production of IL10. These findings show that interindividual differences in IL10 protein levels can be explained at the transcriptional level.

Chromosome Mapping↗

PubMed2004

Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming.

With the increase in life expectancy, death from cardiovascular disease has risen greatly. There is increasing evidence that inflammation plays an important role in cardiovascular disease. We postulate that the development of cardiovascular disease in old age is a late consequence of evolutionary programming for a pro-inflammatory response to resist infections in early age. In 311 women, aged 85 yr old, the production of the pro- and anti-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined in lipopolysaccharide-stimulated whole blood samples and studied prospectively in association with cardiovascular mortality. High TNF-alpha was a risk factor for death from cardiovascular disease (relative risk [RR] = 1.56; 95% confidence interval [CI]: 1-2.40), whereas high IL-10 was protective (RR = 0.58; 95% CI: 0.40-0.85). A genetic variant of the IL-10 gene promoter, which is associated with lower IL-10 production, was found to predispose to a 2.8-fold higher cardiovascular mortality risk (95% CI: 1.17-6.60). Reproductive success, which was studied as a measure of evolutionary programming because it trades off with early survival by pro-inflammatory resistance genes, was negatively associated with an increasing production of TNF-alpha (RR = 0.77; 95% CI: 0.68-0.88), while a positive association with IL-10 was found (RR = 1.22; 95% CI: 1.05-1.41). We suggest that cardiovascular mortality is a late consequence of evolutionary programming for a pro-inflammatory response.

Adult↗

PubMed2004

Combined association and linkage analysis applied to the APOE locus.

Combined association and linkage analysis is a powerful tool for pinpointing functional quantitative traits (QTLs) responsible for regions of significant linkage identified in genome-wide scans. We applied this technique to apoE plasma levels and the APOEepsilon2/epsilon3/epsilon4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome 19, short tandem repeats and the APOEepsilon2/epsilon3/epsilon4 polymorphism were genotyped in adolescent (aged 13-22 years) and adult (aged 34-62 years) Dutch twins. In both samples, evidence for indicative linkage with plasma apoE levels was found (maximum LOD score (MLS)=0.8, MLS=2.5, respectively) at 19q13.32. These linkage regions included the APOE locus. As expected, the APOEepsilon2/epsilon3/epsilon4 polymorphism was strongly associated with apoE plasma levels in both samples. An extension of the between/within families association test developed by Fulker et al. ([1999] Am. J. Hum. Genet. 64:259-267) showed that these associations were not due to population stratification. The combined association and linkage analyses revealed that the association of the APOEepsilon2/epsilon3/epsilon4 polymorphism with apoE plasma levels completely explained the linkage in the adolescent twins and partly in the adult twins.

Adolescent↗

PubMed2004

Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study.

Aging is associated with an impaired capacity of the immune system to respond properly to danger signals, such as infection and cancer. Here, we provide evidence that an impaired innate immune response, as measured by a low production capacity of pro- and anti-inflammatory cytokines upon ex vivo standardized danger signalling with bacterial LPS, is predictive for frailty in elderly people: participants who at age 85-year produced low levels of LPS-induced IL-1beta, IL-6, TNF-alpha and IL-1Ra and IL-10, were found to have a more than 2-fold elevated overall mortality risk, independent of chronic illnesses (relative risk is 2.21, 95% confidence interval 1.27-3.82, P = 0.005), compared to peers with a higher production of any of the pro- and/or anti-inflammatory cytokines. A significant genetic association with the IL-10 promoter gene was found, indicating that people who are genetically predisposed low cytokine producers are at a higher risk of losing the capacity to respond properly to danger signals with aging. We conclude that a malfunctioning innate immune response predicts frailty in old age and is under specific (immuno-) genetic control.

Aged↗

PubMed2004

Further evidence for a QTL influencing body mass index on chromosome 7p from a genome-wide scan in Dutch families.

Obesity is a rapidly growing threat to public health, driven by the increased occurrence of high caloric diets and sedentary lifestyles. Within this environment, genetic influences may largely determine inter-individual differences in obesity-related traits. To map genes involved in weight regulation, we performed a genome-wide linkage scan for body mass index (BMI), a reliable measure of total body fat, in 192 Dutch families including 315 twins and 210 siblings with data on BMI. Using variance components linkage analysis, regions with LOD-scores greater than 2 were observed on 6p25.1 (LOD-score, 2.13) and 7p21.1 (LOD-score, 2.40). LOD-scores higher than 1 were found on chromosomes 3, 13, 15 and 21. Of note, evidence for the putative quantitative trait locus for BMI on 7p was obtained previously from such diverse populations as Mexican-Americans, Asians and Nigerians, suggesting that the underlying genes may effect weight regulation in diverse environments. An obvious positional candidate in the 7p linkage region is the gene encoding neuropeptide Y (NPY) that controls satiety and food intake.

Adolescent↗

PubMed2003

A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer.

Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. A common Ala(222)/Val variant in the methylenetetrahydrofolate reductase (MTHFR) gene leads to a disturbed folate metabolism and is associated with decreased genomic DNA methylation. We previously reported that the MTHFR Val/Val genotype was associated with increased cancer mortality in men from a population-based cohort of subjects ages > or = 85 years. To further explore the deleterious effects of the MTHFR genotype, we studied the association of the genotype with cancer risk in 860 men ages 65-84 years who were followed >10 years (Zutphen Elderly Study). During follow-up, 149 new cases of cancer occurred among the 793 men without cancer at baseline. The risk of developing cancer was 1.80-fold (95% confidence interval, 1.09-3.00) higher among men with the Val/Val genotype than among men with the Ala/Ala genotype. Except for lung cancer [relative risk (RR), 1.15], the risks of common forms of cancers were significantly increased among men with the Val/Val genotype [cancer of the prostate (RR, 3.48); the colorectum (RR, 3.65); the kidney and bladder (RR, 5.48)]. The risks of cancer were particularly increased among men with a lower folate and a higher alcohol intake and men of an older age. In conclusion, our current and previous studies in two independent populations indicate that a common Ala/Val variant in the MTHFR gene is a risk factor for cancer in elderly men from the general population. The mechanism underlying this association might involve genomic instability as a result of insufficient methylation of genomic DNA.

Aged↗

PubMed2003

Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population.

The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors multiple genes that have been suggested to play a role in lipid metabolism and previous studies indicated the presence of a quantitative trait locus (QTL) for cholesterol levels in genetic isolates. To establish the relevance of genetic variation at chromosome 19 for plasma levels of lipids and apolipoproteins in the general, out-bred Caucasian population, we performed a linkage study in four independent samples, including adolescent Dutch twins and adult Dutch, Swedish and Australian twins totaling 493 dizygotic twin pairs. The average spacing of short-tandem-repeat markers was 6-8 cM. In the three adult twin samples, we found consistent evidence for linkage of chromosome 19 with LDL cholesterol levels (maximum LOD scores of 4.5, 1.7 and 2.1 in the Dutch, Swedish and Australian sample, respectively); no indication for linkage was observed in the adolescent Dutch twin sample. The QTL effects in the three adult samples were not significantly different and a simultaneous analysis of the samples increased the maximum LOD score to 5.7 at 60 cM pter. Bivariate analyses indicated that the putative LDL-C QTL also contributed to the variance in ApoB levels, consistent with the high genetic correlation between these phenotypes. Our study provides strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL-C plasma levels in outbred Caucasian populations.

Adolescent↗

PubMed2003

Two-locus linkage analysis applied to putative quantitative trait loci for lipoprotein(a) levels.

Plasma levels of lipoprotein(a) - Lp(a) - are associated with cardiovascular risk (Danesh et al., 2000) and were long believed to be influenced by the LPA locus on chromosome 6q27 only. However, a recent report of Broeckel et al. (2002) suggested the presence of a second quantitative trait locus on chromosome 1 influencing Lp(a) levels. Using a two-locus model, we found no evidence for an additional Lp(a) locus on chromosome 1 in a linkage study among 483 dizygotic twin pairs.

Adolescent↗

PubMed2002

Association of APOE epsilon2/epsilon3/epsilon4 and promoter gene variants with dementia but not cardiovascular mortality in old age.

The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE epsilon4 allele were associated with a 4.1-fold (95% CI, 2.2-7.7) increased risk of dementia as compared to the epsilon3/epsilon3 genotype in old subjects. Moreover, homozygosity for the -219T allele was found to be associated with a 2.4-fold (95% CI, 1.0-5.8) increased risk independently of epsilon2 and epsilon4; the -491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among epsilon4 carriers (RR, 0.6; 95% CI, 0.4-1.0) or -219T homozygous subjects (RR, 1.1; 95% CI, 0.7-1.7), nor did it decrease among -491T homozygous subjects (RR, 1.4; 95% CI, 0.6-3.1). In conclusion, both the APOE epsilon2/epsilon3/epsilon4 and the -219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age.

Age Factors↗

PubMed2002

Heritabilities of apolipoprotein and lipid levels in three countries.

This study investigated the influence of genes and environment on the variation of apolipoprotein and lipid levels, which are important intermediate phenotypes in the pathways toward cardiovascular disease. Heritability estimates are presented, including those for apolipoprotein E and AII levels which have rarely been reported before. We studied twin samples from the Netherlands (two cohorts; n = 160 pairs, aged 13-22 and n = 204 pairs, aged 34-62), Australia (n = 1362 pairs, aged 28-92) and Sweden (n = 302 pairs, aged 42-88). The variation of apolipoprotein and lipid levels depended largely on the influences of additive genetic factors in each twin sample. There was no significant evidence for the influence of common environment. No sex differences in heritability estimates for any phenotype in any of the samples were observed. Heritabilities ranged from 0.48-0.87, with most heritabilities exceeding 0.60. The heritability estimates in the Dutch samples were significantly higher than in the Australian sample. The heritabilities for the Swedish were intermediate to the Dutch and the Australian samples and not significantly different from the heritabilities in these other two samples. Although sample specific effects are present, we have shown that genes play a major role in determining the variance of apolipoprotein and lipid levels in four independent twin samples from three different countries.

Adolescent↗